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Drug Substitutes for Training to Blunt Fears in Rats

Researchers were able to reduce a conditioned fear in rats by
using a drug, mimicking the effect of training. The finding suggests
new possibilities for treating anxiety disorders.

Each year anxiety disorders affect an estimated 40 million adults
nationwide. Unlike the relatively mild, brief anxiety caused by
a stressful event (such as speaking in public or a first date),
anxiety disorders cause fearfulness and uncertainty that lasts
at least 6 months and can get worse if untreated. While effective
therapies are available, an understanding of the molecular mechanisms
behind anxiety disorders could lead to better treatments.

Rats serve as a useful model for studying anxiety. Rats freeze
when they hear a tone they've been conditioned to associate with
an electric shock. This reaction can be reversed by "extinction
training" — repeatedly exposing the rats to the tone
with no shock. Past studies have shown that extinction training
doesn't erase a previously conditioned fear memory. Rather, it
creates a new memory associating the tone with safety.

Memory formation involves changes in the connections, or synapses,
between neurons. This capacity for change is called synaptic plasticity.
A brain region called the infralimbic prefrontal cortex (ILC) is
known to be critical for extinction memory in rats. Drugs that
block synaptic plasticity impair extinction learning when injected
into the ILC, causing rats to continue freezing at high levels
after extinction training.

Previous research implicated a protein called brain-derived neurotrophic
factor (BDNF) in extinction learning. BDNF is one of a class of
proteins known to support the growth and survival of neurons, permitting
a learning experience to increase the size and strength of synaptic
contacts between neurons.

A research team led by Dr. Gregory Quirk at the University of
Puerto Rico School of Medicine set out to study BDNF’s role
in extinction learning. They conditioned rats to fear a tone by
pairing it with a footshock. They then infused BDNF directly into
the ILC. Their work was funded by NIH’s National Institute
of Mental Health (NIMH), National Institute of Neurological Disorders
and Stroke (NINDS) and National Center for Research Resources (NCRR).

As detailed in the June 4, 2010, issue of Science, infusing
BDNF directly into the ILC enhanced extinction training. Even before
extinction training, the researchers noticed that freezing was
significantly reduced in the BDNF rats. So they repeated their
experiments without extinction training and found that the BDNF-infused
rats showed little freezing to the tone the next day.

"The surprising finding here is that the drug substituted
for extinction training," Quirk says.

BDNF didn't reduce general anxiety or change the animals’ tendency
to move around. Further experiments showed that it also didn’t
erase the original fear memory.

The researchers compared the brains of various rats after extinction
training. Rats with lower BDNF levels were less likely to succeed
in extinction training.

"Many lines of evidence implicate BDNF in mental disorders," says
NIMH Director Dr. Thomas Insel. "This work supports the idea
that medications could be developed to augment the effects of BDNF,
providing opportunities for pharmaceutical treatment of post-traumatic
stress disorder and other anxiety disorders."